Efficacy and Safety of Weekly Somatrogon vs Daily Somatropin in Children With Growth Hormone Deficiency: A Phase 3 Study

Cheri L Deal, Joel Steelman, Elpis Vlachopapadopoulou, Renata Stawerska, Lawrence A Silverman, Moshe Phillip, Ho-Seong Kim, CheolWoo Ko, Oleg Malievskiy, Jose F Cara, Carl L Roland, Carrie Turich Taylor, Srinivas Rao Valluri, Michael P Wajnrajch, Aleksandra Pastrak, Bradley S Miller, Cheri L Deal, Joel Steelman, Elpis Vlachopapadopoulou, Renata Stawerska, Lawrence A Silverman, Moshe Phillip, Ho-Seong Kim, CheolWoo Ko, Oleg Malievskiy, Jose F Cara, Carl L Roland, Carrie Turich Taylor, Srinivas Rao Valluri, Michael P Wajnrajch, Aleksandra Pastrak, Bradley S Miller

Abstract

Context: Somatrogon is a long-acting recombinant human growth hormone (rhGH) in development for once-weekly treatment of children with growth hormone deficiency (GHD).

Objective: We aimed to compare the efficacy and safety of once-weekly somatrogon with once-daily somatropin in prepubertal children with GHD.

Methods: In this 12-month, open-label, randomized, active-controlled, parallel-group, phase 3 study, participants were randomized 1:1 to receive once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. A total of 228 prepubertal children (boys aged 3-11 years, girls aged 3-10 years) with GHD, impaired height and height velocity (HV), and no prior rhGH treatment were randomized and 224 received ≥1 dose of study treatment (somatrogon: 109; somatropin: 115). The primary endpoint was annualized HV at month 12.

Results: HV at month 12 was 10.10 cm/year for somatrogon-treated subjects and 9.78 cm/year for somatropin-treated subjects, with a treatment difference (somatrogon-somatropin) of 0.33 (95% CI: -0.24, 0.89). The lower bound of the 2-sided 95% CI was higher than the prespecified noninferiority margin (-1.8 cm/year), demonstrating noninferiority of once-weekly somatrogon vs daily somatropin. HV at month 6 and change in height standard deviation score at months 6 and 12 were similar between both treatment groups. Both treatments were well tolerated, with a similar percentage of subjects experiencing mild to moderate treatment-emergent adverse events in both groups (somatrogon: 78.9%, somatropin: 79.1%).

Conclusion: The efficacy of once-weekly somatrogon was noninferior to once-daily somatropin, with similar safety and tolerability profiles. (ClinicalTrials.gov no. NCT02968004).

Keywords: growth hormone; growth hormone deficiency; long-acting growth hormone; pediatric; somatrogon; somatropin.

© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.

Figures

Figure 1.
Figure 1.
(A) Study design and (B) subject disposition. aSubjects who were in screening when enrollment target was met, and therefore not randomized to study treatment.
Figure 2.
Figure 2.
Subgroup analyses for the primary endpoint of height velocity at month 12. a[n1, n2] represents the sample sizes for somatrogon and somatropin, respectively, within each subgroup. Region 1: Western Europe, Israel, Greece, Australia, New Zealand, Canada, and USA. Region 2: Central and Eastern Europe, Turkey, Latin America, and Asia, except for India and Vietnam. Region 3: India and Vietnam. Abbreviations: GH, growth hormone; LSM, least squares mean.
Figure 3.
Figure 3.
Summary of (A) height velocity and (B) height SDS over time. Baseline is defined as the last non-missing measurement prior to the start of study drug. Abbreviation: SDS, standard deviation score.
Figure 4.
Figure 4.
IGF-1 SDS over time. Abbreviation: SDS, standard deviation score.

References

    1. Brod M, Hojbjerre L, Alolga SL, Beck JF, Wilkinson L, Rasmussen MH. Understanding treatment burden for children treated for growth hormone deficiency. Patient. 2017;10(5):653-666.
    1. Graham S, Auyeung V, Weinman J. Exploring potentially modifiable factors that influence treatment non-adherence amongst pediatric growth hormone deficiency: a qualitative study. Patient Prefer Adherence. 2020;14:1889-1899.
    1. Christiansen JS, Backeljauw PF, Bidlingmaier M, et al. . Growth Hormone Research Society perspective on the development of long-acting growth hormone preparations. Eur J Endocrinol. 2016;174(6):C1-C8.
    1. Cutfield WS, Derraik JG, Gunn AJ, et al. . Non-compliance with growth hormone treatment in children is common and impairs linear growth. PLoS One. 2011;6(1):e16223.
    1. Hughes IP, Choong C, Rath S, et al. . Early cessation and non-response are important and possibly related problems in growth hormone therapy: An OZGROW analysis. Growth Horm IGF Res. 2016;29:63-70.
    1. Wit JM, Deeb A, Bin-Abbas B, Al Mutair A, Koledova E, Savage MO. Achieving optimal short- and long-term responses to paediatric growth hormone therapy. J Clin Res Pediatr Endocrinol. 2019;11(4):329-340.
    1. Farfel A, Shalitin S, Morag N, Meyerovitch J. Long-term adherence to growth hormone therapy in a large health maintenance organization cohort. Growth Horm IGF Res. 2019;44:1-5.
    1. Koledova E, Stoyanov G, Ovbude L, Davies PSW. Adherence and long-term growth outcomes: results from the easypod() connect observational study (ECOS) in paediatric patients with growth disorders. Endocr Connect. 2018;7(8):914-923.
    1. Savendahl L, Battelino T, Rasmussen MH, Brod M, Saenger P, Horikawa R. Effective GH replacement with once-weekly somapacitan vs daily GH in children with GHD: 3-year results from REAL 3. J Clin Endocrinol Metab. Published online ahead of print December, 2021. doi:10.1210/clinem/dgab928
    1. Thornton PS, Maniatis AK, Aghajanova E, et al. . Weekly lonapegsomatropin in treatment-naive children with growth hormone deficiency: the phase 3 heiGHt trial. J Clin Endocrinol Metab. 2021;106(11):3184-3195.
    1. Loftus J, Quitmann J, Valluri S, Pastrak A, Reiter L, Roland C. Comparison of quality of life responses from caregiver and children aged ≥7 years using the Quality of Life In Short Stature Youth (QoLISSY) questionnaire, following 12 months of growth hormone treatment with either a weekly somatrogon or a daily genotropin injection schedule. J Endocr Soc. 2021;5(Suppl_1):A674-A674.
    1. van den Wijngaard L, Rodijk ICM, van der Veen F, et al. . Patient preference for a long-acting recombinant FSH product in ovarian hyperstimulation in IVF: a discrete choice experiment. Hum Reproduct. 2014;30(2):331-337.
    1. Djambas Khayat C. Once-weekly prophylactic dosing of recombinant factor IX improves adherence in hemophilia B. J Blood Med. 2016;7:275-282.
    1. Escobar M, Santagostino E, Mancuso ME, et al. . Switching patients in the age of long-acting recombinant products? Expert Rev Hematol. 2019;12(sup1):1-13.
    1. Fares FA, Suganuma N, Nishimori K, LaPolt PS, Hsueh AJ, Boime I. Design of a long-acting follitropin agonist by fusing the C-terminal sequence of the chorionic gonadotropin beta subunit to the follitropin beta subunit. Proc Natl Acad Sci USA. 1992;89(10):4304-4308.
    1. Pouwer AW, Farquhar C, Kremer JA, Marjoribanks J. Long-acting follicle-stimulating hormone versus daily follicle-stimulating hormone for women undergoing assisted reproduction. Fertil Steril. 2016;105(6):1454-1456.
    1. Fares F, Havron A, Fima E. Designing a long acting erythropoietin by fusing three carboxyl-terminal peptides of human chorionic gonadotropin beta subunit to the N-terminal and C-terminal coding sequence. Int J Cell Biol. 2011;2011:275063.
    1. Hershkovitz O, Bar-Ilan A, Guy R, et al. . In vitro and in vivo characterization of MOD-4023, a long-acting carboxy-terminal peptide (CTP)-modified human growth hormone. Mol Pharm. 2016;13(2):631-639.
    1. Strasburger CJ, Vanuga P, Payer J, et al. . MOD-4023, a long-acting carboxy-terminal peptide-modified human growth hormone: results of a Phase 2 study in growth hormone-deficient adults. Eur J Endocrinol. 2017;176(3):283-294.
    1. Zelinska N, Iotova V, Skorodok J, et al. . Long-acting C-terminal peptide-modified hGH (MOD-4023): results of a safety and dose-finding study in GHD children. J Clin Endocrinol Metab. 2017;102(5):1578-1587.
    1. Zadik Z, Zelinska N, Iotova V, et al. . Results from an open-label extension of the phase 2 dose finding study of once weekly somatrogon vs daily genotropin in pediatric patients with growth hormone deficiency (GHD). J Endocr Soc. 2021;5(Suppl_1):A684-A685.
    1. Deal C, Cara J, Kim H-S, et al. . Data from: Efficacy and safety of weekly somatrogon vs daily somatropin in children with growth hormone deficiency: a phase 3 study. Figshare Digital Repository. Deposited March 10, 2022. .
    1. Centers for Disease Control. Growth charts. 2010 (last update: Sep 9, 2010). Accessed June 22, 2021.
    1. Greulich WW, Pyle SJ.. Radiographic Atlas of Skeletal Development of the Hand and Wrist. 1st ed. Palo Alto: Stanford University Press; 1959; 1-272.
    1. Bidlingmaier M, Friedrich N, Emeny RT, et al. . Reference intervals for insulin-like growth factor-1 (IGF-1) from birth to senescence: results from a multicenter study using a new automated chemiluminescence IGF-I immunoassay conforming to recent international recommendations. J Clin Endocrinol Metab. 2014;99(5):1712-1721.
    1. Fisher DM, Rosenfeld RG, Jaron-Mendelson M, Amitzi L, Koren R, Hart G. Pharmacokinetic and pharmacodynamic modeling of MOD-4023, a long-acting human growth hormone, in growth hormone deficiency children. Horm Res Paediatr. 2017;87(5):324-332.
    1. Ciresi A, Ciccio F, Amato MC, Giordano C. Revaluation of the clinical and metabolic behavior of children with isolated growth hormone deficiency during GH treatment according to newly proposed note 39 of the Italian Medicines Agency (AIFA). J Endocrinol Invest. 2015;38(12):1301-1307.
    1. Witkowska-Sedek E, Labochka D, Stelmaszczyk-Emmel A, et al. . Evaluation of glucose metabolism in children with growth hormone deficiency during long-term growth hormone treatment. J Physiol Pharmacol. 2018;69(2). doi:10.26402/jpp.2018.2.08
    1. Allen DB, Backeljauw P, Bidlingmaier M, et al. . GH safety workshop position paper: a critical appraisal of recombinant human GH therapy in children and adults. Eur J Endocrinol. 2016;174(2):P1-P9.
    1. Bidlingmaier M, Schilbach K. The use of IGF-I to monitor long-acting growth hormone therapy-timing is an art. J Clin Endocrinol Metab. 2021;106(5):e2367-e2369.
    1. Yuen KCJ, Miller BS, Boguszewski CL, Hoffman AR. Usefulness and potential pitfalls of long-acting growth hormone analogs. Front Endocrinol (Lausanne). 2021;12:637209.
    1. Savendahl L, Battelino T, Brod M, Hojby Rasmussen M, Kildemoes RJ, Saenger P. Letter to the editor from L. Savendahl et al.: “Weekly lonapegsomatropin in treatment-naive children with growth hormone deficiency: the phase 3 heiGHt trial”. J Clin Endocrinol Metab. 2022;107(2):e888-e889.
    1. Thornton PS, Maniatis AK, Aghajanova E, et al. . Response to letter to the editor from L. Sävendahl et al: “Weekly lonapegsomatropin in treatment-naïve children with growth hormone deficiency: the phase 3 heiGHt trial”. J Clin Endocrinol Metab. 2022;107(3):e1333-e1334.
    1. Kremidas D, Wisniewski T, Divino VM, et al. . Administration burden associated with recombinant human growth hormone treatment: perspectives of patients and caregivers. J Pediatr Nurs. 2013;28(1):55-63.
    1. McNamara M, Turner-Bowker DM, Westhead H, et al. . Factors driving patient preferences for growth hormone deficiency (GHD) injection regimen and injection device features: a discrete choice experiment. Patient Prefer Adher. 2020;14:781-793.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться